Cilostazol exerts potent anti-inflammatory effects and
celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of
NSAIDs. It was aimed to assess the anti-arthritic potential of
celecoxib add-on for
cilostazol therapy in
collagen induced arthritis (CIA), and to elucidate the implication of
interleukin (IL)-10 in the action of
cilostazol and
celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 μM
cilostazol and 0.3 μM
celecoxib synergistically suppressed RANKL-induced increases in RANK
mRNA and
protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and
cathepsin K mRNA) and the expression of RANK
mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with
cilostazol (10 μM) and
celecoxib (0.3 μM). In addition, this co-treatment strongly down-regulated RANKL-induced
NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with
IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of
M-CSF/RANKL were markedly suppressed by
cilostazol and
celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by
cilostazol (10 mg/kg/d) and
celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in
arthritis scores in the CIA mice. In conclusion, serum
IL-10 levels in these mice were markedly increased by
cilostazol and
celecoxib cotreatment, whereas elevated serum IL-1β levels were markedly reduced. Cotreatment with low-dose
cilostazol and
celecoxib may ensure the synergistic anti-arthritic potential.